Inflammatory nature of atherosclerosis and the vulnerability of the plaque have suggested the need to identify agents that would inhibit these processes in the treatment of the disease. We recently observed that the administration of sesame oil to atherosclerotic mice not only reduced the blood lipids by 50% but also prevented atherosclerosis by over 85%. Preliminary results indicated that sesame oil inhibited the expression of pro-inflammatory genes and genes related to plaque vulnerability while it enhanced the expression of genes involved in reverse cholesterol transport. There are two potential possibilities-.-these effects are due hitherto unknown effects of the fatty acid constituents of sesame oil (It contains almost equal amounts of mono and polyunsaturated fatty acids), or due to its unusual non-saponifiable components. The results also posed an important question, whether lowering of plasma lipids themselves resulted in the decrease of inflammation and promoted plaque stability and increased reverse cholesterol transport or the gene effects of sesame oil or its constituents were responsible for the observed decrease in lipids and atherosclerosis. Sesame oil contains equal amounts of mono- and poly unsaturated fatty acids and contains bio-active non-saponifiable components that are potent antioxidants and PPAR1 agonists. The overall goal of the study is to determine the mechanisms by which fatty acid components and non- saponifiable components of sesame oil could exert beneficial in atherosclerosis. In lieu of vitamin E's failure in protecting human atherosclerosis, identification of the mechanisms by which the non-saponifiable components of sesame oil might complement the anti-atherosclerotic effects of dietary unsaturated fat could lead to major new pharmacological alternatives and directions. The Goals of the proposed studies are: 1. To compare the efficacy of sesame oil with sunflower oil in its anti-atherosclerotic effects with using LDL receptor knockout animals and to delineate and identify the anti-atherosclerotic effects of its non- saponifiable components. 2. Identify the anti-atherosclerotic genes that are regulated by sesame oil and its saponifiable and non- saponifiable components and to define potential molecular mechanisms that may be involved in their action. 3. To determine whether sesame oil supplementation decrease markers of cardiovascular risk in normal and high risk human subjects. Implications: Dietary prevention of atherosclerosis has major advantages to pharmacological control, being inexpensive, sensible, and healthy. The proposed study could lead to the identification of components that could be cheap alternatives to expensive medication offering valuable adjunct therapy to existing medications, It would also lead to new class of drug development.